Abstract The endocannabinoid system, consisting of the CB1R and lipid derived endogenous cannabinoid molecules, has been shown to significantly contribute to the development of diabetes and obesity. Although CB1R inverse agonists are effective at improving insulin sensitivity and protecting against diet induced obesity, these drugs have severe side effects associated with the widespread distribution of CB1Rs in the CNS and the periphery. The goal of this application is to investigate the role of CB1Rs in the SF1 neurons of the ventromedial hypothalamus to regulate energy homeostasis. We will also examine if this subset of neurons is responsible for the metabolic improvements associated with CB1R inverse agonists. We anticipate the results from our investigation will provide novel insight to the development of effective therapies to combat metabolic disease while circumventing potential side effects.